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MRI and uterine biopsy were used to diagnose nodular adenomyosis by Phillips et al. 1996 ; . Preoperative GnRH analogue, endomyometrial resection and bipolar coagulation were used in 14 women. One year after treatment menorrhagia was cured in 12 and dysmenorrhoea in eight. Two proceeded to hysterectomy. The advantage of preoperative use of GnRH analogue was shown by a 50.8% mean reduction of uterine volume after leuprolide acetate treatment for 3 months. A further 14.9% mean reduction occurred after the surgery. The beneficial effect of leuprolide may have continued for at least 3 months after surgery so that a 1 year follow-up assessment may give a favourable view of the efficacy of the surgery. In 10 patients laparoscopic bipolar coagulation alone was performed on adenomyomata, and seven of 10 women had symptom relief after 1 year, one requiring hysterectomy Phillips et al., 1996 ; . In a year follow-up Table I ; the results were similar following electrocoagulation without the use of a GnRH analogue. Endomyometrial ablation alone may be successful in curing symptoms of menorrhagia and dysmenorrhoea Table I; Phillips et al., 1996 ; . Using rollerball ablation and performing a posterior uterine wall biopsy prior to this to determine the depth of penetration shows that those with minimal penetration had a good outcome and those with deep penetration a poor outcome. The authors recommended hysterectomy in the presence of deep penetration as a rollerball procedure would only cause necrosis in the superficial 23 mm of the myometrium. An electrical loop, because endep 10 side effects.
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Chairman: Dr D Farquhar, Consultant Physician, St. John's Hospital, Livingston, Scotland But will it do me any good, Doctor? Dr S Maxwell, Consultant Physician, University of Edinburgh, Edinburgh, Scotland Abstract Not available at the time of going to press. Preventing falls in institutions Dr D Oliver, Senior Lecturer, Elderly Care Medicine, University of Reading, Reading, England Email d.oliver reading.ac Abstract Background Falls in hospitals and care homes are common and problematic for individuals, institutions, governance and risk management. They bring about physical, psychological and ascorbic, because endep migraine.
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| Endep wikiMETHODS Model structure: Pharmacokinetic component. The transport and dispositional kinetics of T and DHT are described using standard PBPK compartmental modeling 32 ; , while a single compartmental model is used for LH. Flow-limited compartments are utilized in cases where the uptake rate of a compound into a tissue is limited by the blood flow rate into the tissue rather than the diffusion rate of the compound across cell membranes. Conversely, diffusion-limited compartments are used when the diffusion across cell membranes is slow compared to the blood flow rate into the tissue 32 ; . The pharmacokinetics of T and DHT are modeled with compartments representing the systemic serum, liver, prostate, testes and rest of body see Figure.
A 96-well plate reader MR7000; Dynatech, Chantilly, VA ; . All of the experiments were run in sextuplicate. Flow Cytometry-based Apoptosis Assay. Untreated, BP-treated, and Taxol-treated endothelial cells were harvested with trypsin-EDTA, and resuspended in phosphate-buffered saline containing 2% m v ; bovine serum albumin 106 cells ml for each experimental condition ; . Detection of apoptosis in endothelial cells in suspension was performed using the TACS Annexin V apoptosis detection kit R&D Systems Europe, Abingdon, United Kingdom ; . The staining was analyzed on a Galaxy flow cytometer Dako, Trappes, France ; as described previously 6 ; . Capillary-like Tube Formation Assay. The surface of 24-well plates was coated with the basement membrane Matrigel 400 l well; 10 mg ml ; in the presence or absence of increasing concentrations of different BPs. Matrigel was then allowed to polymerize at 37C for 30 min. Endothelial cells were laid on Matrigel-coated plates in the presence of complete medium 4 104 cells ml well ; . After a 16-h incubation at 37C in a 5% CO2 incubator, the wells were photographed. The total length of the tube network on photographed well areas was measured using a semiautomatic analyzer Videoplan, Kontron, Munich, Germany ; , and results were expressed as m cm2. Cell Transfection and Luciferase Activity Measurement. Androgendependent LNCaP prostatic cells gift from Dr. Leland Chung, University of Virginia Health Science Center, Charlottesville, VA ; were grown in DMEM Invitrogen, Cergy Pontoise, France ; supplemented with 5% v v ; FCS, 5 mg ml insulin Sigma ; , 13.6 pg ml triiodothyronine Sigma ; , 5 mg ml apo-transferrin Sigma ; , 0.25 mg ml biotin Sigma ; , 25 mg ml adenine Sigma ; , 100 units ml penicillin Invitrogen ; , and 100 mg ml streptomycin Invitrogen ; . Cells were transiently transfected overnight using the calcium phosphate precipitation method with a luciferase gene reporter vector containing or not containing four times androgen-responsive-elements in the promotor 500 ng, gift from Dr. Chinghai Kao, Indiana University School of Medicine, Indianapolis, IN; Ref. 14 ; . After transfection, cells were washed and refed with fresh complete medium. After a 10-h incubation, cells were washed again then treated with a synthetic analogue of testosterone R1881; NEN, Zaventem, Belgium; 10 ng ml in DMEM ; in the presence or absence of increasing concentrations of zoledronic acid. Twenty-four h later, cells were solubilized, and the luciferase activity was measured using a luminometer Analogical Luminescence Laboratory ; . Quantification of the Vascularization in Bone Biopsy Specimens from Patients with Paget's Disease before and after Clodronate Treatment. The effect of clodronate treatment on clinical, biochemical, and histomorphometrical evaluation of patients with Paget's disease has been published previously 12, 15 ; . Twenty-three patients received a daily treatment with clodronate for 6 months. These patients were randomly assigned to receive 400, 800, 1600, or 2400 mg day of clodronate. For each patient, a transiliac bone biopsy was performed before therapy and after 6 months of treatment. For each bone biopsy, microvessels present in the bone marrow were enumerated microscopically at a high magnification 20, area 0.142 mm2 ; in five nonoverlapping HPFs. The microvessel score for each biopsy was expressed as the mean counts per HPF. Each evaluation was performed independently by two examiners and was done in a blinded fashion. In case of disagreement between examiners, bone biopsies were reviewed and a consensus opinion was obtained. Animals, Treatments, and Immunohistochemistry. All of the procedures were performed on adult male Sprague Dawley rats weight 330 grams; IFFA CREDO, Saint Germain sur l'Arbresle, France ; . Studies involving animals, including housing, care, method of euthanasia, and experimental protocols, were conducted in accordance with a code of practice established by the local animal ethical committee in Lyon. Franck-Lissbrant et al. 16 ; have shown that castration induces regression, and testosterone stimulates regrowth of the prostatic vasculature in castrated rats, suggesting that this experimental model can be used to study factors regulating angiogenesis in the prostate. Therefore, the castration of animals and the administration of testosterone were performed according to the protocol described by these authors 16 ; . Twenty-one days after castration, animals received a s.c. pellet of long-acting testosterone 15 mg pellet; Innovative Research of America, Sarasota, FL ; for 6 days. On testosterone treatment, rats were randomized into groups of 510 animals, and then received either a BP or the vehicle PBS; pH 7.0 ; , administrated s.c. at doses ranging from 5 to 100 g kg day for 6 days. At sacrifice, on day 6, the ventral prostate was dissected, formalin-fixed, and paraffin-embedded and tenoretic.
1 month ; TAM treatment, MAPK activity was higher in tumor xenografts than after long-term 5 month ; treatment Table 2 ; , suggesting the importance of early changes in this activity for the subsequent development of hypersensitivity to E2 and resistance to TAM. One of the primary aims of this study was to examine the effects of TAM on the level of sensitivity to E2. We clearly showed that this takes place in tumor xenografts exposed to TAM for 5 months. Rather low doses of E2 equivalent to 20 pg plasma ; stimulate the growth of these TAMpretreated tumors but not those previously exposed to vehicle. This increase in sensitivity appears to be specific for breast tumors since the uterus appeared more sensitive to E2 in the vehicle-treated animals. Notably, hypersensitivity in response to estrogen was more evident in MCF-7 xenografts treated with TAM in vivo Table 1 and performed with Dr Mark Conaway, analysis of individual slopes of tumor growth; LM Bernstein, J-P Wang, H Zeng, W Yue, M Conway & RJ Santen, data not shown ; than in cells exposed to TAM in vitro. Perhaps long-term exposure to TAM is required in vitro to acquire the hypersensitive phenotype. We are continuing the in vitro exposure to TAM in order to assess this possibility. We were not able to detect gradual increases in activation of MAPK or aromatase in human breast cancers unsuccessfully treated with TAM nor in tissue of tumor xenografts in nude mice by the end of TAM treatment. It should be mentioned that TAM has not been considered so far among factors influencing aromatase activity Dowsett et al. 1993, Miller & Mullen 1993 ; . It remains unknown whether and how the process of local estrogen production in breast cancer cells is involved in the first steps and further maintenance of TR. However, this remains an area for further investigation as suggested by several trends reflected by our data. For example, we observed a time-dependent increase of aromatase activity in association with TAM administration in wild-type MCF-7 cells or in 1 month TAM-treated xenografts. In addition, there was an association between shifts in aromatase and in tumor pathology neo-adjuvant course ; and between changes in aromatase and tumor estrogen receptor content adjuvant course ; . Several recent publications have described an `interrelationship' between TAM exposure and MAPK activity Donovan et al. 2001, Gee et al. 2001, Adeyinka et al. 2002, Atanaskova et al. 2002, Rabenoelina et al. 2002 ; . As demonstrated in the present investigation, MAPK activity is higher in estrogen-deprived MCF-7 cells which reproduces results of Jeng et al. 2000 ; as well as in the same cells treated with TAM at least temporarily ; and in established TAM-resistant cell lines Fig. 3 ; . Additionally this activity is higher in tumor xenografts in mice treated with TAM during 1 month vs 5 months ; and in primary human breast cancers before unsuccessful neo-adjuvant TAM treatment than after such courses Tables 2 and 3 ; . Based upon a summary of our own and published data, we suggest together with Rabenoelina et al. 2002 ; that MAPK activation might be involved in early steps during progressive reshaping of the cells toward a TR phenotype. Such reshaping may be the result of cellular adaptation that induces after a stage of initial sensitivity to antiestrogenic effect of TAM ; increased reaction to the agonistic action of the drug and finally to a growth-stimulating effect of estrogens. In conclusion, our studies confirmed the complex nature of TR. The major findings of this investigation can be presented here in the following way. Two known types of TR exist: primary and acquired. These differ by certain important characteristics, which probably include the level of the involvement of adaptive and genetic components. Based upon our findings, at least three consequent stages of TR can be distinguished. These stages can be designated as stage I when TAM behaves as an antiestrogen ; , stage II with increased sensitivity to agonistic proestrogenic ; TAM effects and stage III with an adaptive increase in sensitivity to E2. The time frame of the increase in MAPK activity in the course of the development of TR as rule outpaces the increase in aromatase activity and can be one of the promoting factors for the latter. On the other hand, the chronology of these events indicates that changes in the MAPK cascade can be more important for the early steps of the development and maintenance of the TR state. Perhaps changes in local estrogen production sensitivity to E2 are essential for relatively later steps of this phenomenon. FTS reduces the increase in number of MCF-7 cells induced by long-term TAM treatment. It also decreases MAPK activity in TAM-treated MCF-7 cells and in established TR cell lines. Separately or in combination with letrozole presumably, through the influence on MAPK pathway ; FTS moderately inhibits aromatase activity of estrogendeprived or estrogen-enriched MCF-7 cells. Altogether, our observations suggest that FTS is a `candidate drug' for the treatment of TR of both adaptive and genetic types. Results from these studies suggest the possible importance of starting the treatment prevention of TR early on. In addition, our data point to the need to find additional criteria predisposing to development of the resistant state. There is a rather strong rationale to include as a predisposing factor the increase in MAPK and aromatase activities in primary breast tumors. Both are directly or indirectly associated with sensitivity of tumor cells to E2 and with genomic non-genomic estrogenic effects Santen et al. 2001, Berstein et al. 2002, Zhang et al. 2002.
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Table 2. Current formulations and dosing recommendations for tricyclic antidepressants 309311 ; * Amitriptyline HCl tablets Elavil, Endepp ; : 10, 25, 50, mg Adults: 40100 mg initially and daily maintenance max 150300 mg daily ; Adolescents & elderly: 10 mg TID and 20 mg q HS maximum: 200 mg daily ; Clomipramine HCl capsules Anafranil ; : 25, 50, 75 mg Adults: 25 mg initially to 100 mg maintenance max 300 mg daily ; Children 1018 years old ; : 25 mg initially to 100 mg or 3mg kg ; maintenance max 200 mg daily ; Desipramine HCl tablets Norpramin ; : 10, 25, 50, mg Adults: 100200 mg max 300 mg daily in hospitalized patients ; Adolescents & elderly: 25100 mg max 150 mg daily ; Child 612 years old ; : 13 mg kg day max 5 mg kg day ; Doxepin HCl capsules Sinequan ; : 10, 25, 50, mg; oral concentrate 10 mg base ; mL Adults: 2575 mg max 300 mg daily max single dose: 150 mg ; Child: 13 mg kg day Doxepin cream Prudoxin, Zonalon ; : 5%; each g 50 mg doxepin HCl As directed QID. Imipramine HCl tablets Norfranil, Tipramine, Impril, Janimine, Novopramine, Tofranil ; : 10, 25, 50 mg Impiramine pamoate capsules Tofranil-PM ; : 75, 100, 125, mg Adults: 75100 mg daily max 200 mg daily; 300 mg daily for hospitalized patients only ; Adolescents & elderly: 3040 mg daily max 100 mg daily ; Children: 5 yr of age 1.52.5 mg kg day max 5 mg kg d ; Child enuresis, in 612 years old ; : 2550 mg at bedtime Child enuresis, in 12 year olds ; 2575 mg max 2.5 mg kg ; Nortriptyline HCl capsules Aventyl, Pamelor ; : 10, 25, 50, mg; oral concentrate 10 mg 5 mL Adults: 25 mg TID or QID max 150 mg daily ; Adolescents & elderly: 3050 mg daily max 50 mg daily ; Children 612 years old: 13 mg kg day or 1020 mg day Protriptyline HCl tablets Vivactil ; : 5, 10 mg Adults: 1540 mg daily in divided doses max 60 mg daily ; Adolescents & elderly: 15 mg daily initially max 20 mg daily ; Trimipramine maleate capsules Surmontil ; : 25, 50, 100 mg Adults: 75100 mg in divided doses max 150 mg outpatients; 200 mg hospitalized patients ; Adolescents & elderly: 50 mg daily max 100 mg daily ; Tricyclic Antidepressants in Combination Perphenazine & amitriptyline HCl tablets Etrafon, Triavil ; : 2 10, 2 mg 50 mg Amitriptyline dosing same as above Chlordiazepoxide & amitriptyline HCl tablets Limbitrol ; : 5 12.5, 10 mg 25 mg Amitriptyline dosing same as above!
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